Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m2. We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 103 per μL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity.

Department of Hematology and Oncology University of California San Diego La Jolla CA United States

Department of Oncology and Radiotherapy University Hospital in Hradec Kralove Hradec Kralove Czechia

Department of Radiation Oncology Tata Memorial Hospital Mumbai India

Department of Radiation Oncology Xijing Hospital Xi'an China

Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology Gliwice Poland

Radiation Medicine and Applied Sciences University of California San Diego La Jolla CA United States

Zobrazit více v PubMed

Georgiou KR, Foster BK, Xian CJ. Damage and recovery of the bone marrow microenvironment induced by cancer chemotherapy – potential regulatory role of chemokine CXCL12/receptor CXCR4 signalling. Curr Mol Med. (2010) 10:440–53. 10.2174/156652410791608243 PubMed DOI

Crawford J, Dale DC, Lyman GH. Chemotherapy-Induced neutropenia: risks, consequences, and new directions for its management. Cancer. (2004) 100:228–37. 10.1002/cncr.11882 PubMed DOI

Elting LS, Rubenstein EB, Martin CG, Kurtin D, Rodriguez S, Laiho E, et al. . Incidence, cost, and outcomes of bleeding and chemotherapy dose modificaton among solid tumor patients with chemotherapy-induced thrombocytopenia. J Clin Oncol. (2001) 19:1137–46. 10.1200/JCO.2001.19.4.1137 PubMed DOI

Abu-Rustum NR, Lee S, Correa A, Massad LS. Compliance with and acute hematologic toxic effects of chemoradiation in indigent women with cervical cancer. Gynecol Oncol. (2001) 81:88–91. 10.1006/gyno.2000.6109 PubMed DOI

Mell LK, Sirák I, Wei L, Tarnawski R, Mahantshetty U, Yashar CM, et al. . Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: an international multicenter phase II clinical trial (INTERTECC-2). Int J Radiat Oncol Biol Phys. (2017) 97:536–45. 10.1016/j.ijrobp.2016.11.027 PubMed DOI

Yeung AR, Pugh SL, Klopp AH, Gil KM, Wenzel L, Westin SN, et al. . Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG oncology RTOG 1203. Study. J Clin Oncol. (2020) 38:1685–92. 10.1200/JCO.19.02381 PubMed DOI PMC

Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. (2015) 1:1325–32. 10.1001/jamaoncol.2015.2756 PubMed DOI

Yan K, Ramirez E, Xie XJ, Gu X, Xi Y, Albuquerque K. Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer. Pract Radiat Oncol. (2018) 8:13–9. 10.1016/j.prro.2017.07.001 PubMed DOI

Noticewala SS, Li N, Williamson CW, Hoh CK, Shen H, McHale MT, et al. . Longitudinal changes in active bone marrow for cervical cancer patients treated with concurrent chemoradiation therapy. Int J Radiat Oncol Biol Phys. (2017) 97:797–805. 10.1016/j.ijrobp.2016.11.033 PubMed DOI

Zhu H, Zakeri K, Vaida F, Carmona R, Dadachanji KK, Bair R, et al. . Longitudinal study of acute haematologic toxicity in cervical cancer patients treated with chemoradiotherapy. J Med Imaging Radiat Oncol. (2015) 59:386–93. 10.1111/1754-9485.12297 PubMed DOI PMC

Dainiak N. Hematologic consequences of exposure to ionizing radiation. Exp Hematol. (2002) 30:513–28. 10.1016/S0301-472X(02)00802-0 PubMed DOI

Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane database Syst Rev. (2005) 20:CD002225 10.1002/14651858.CD002225.pub2 PubMed DOI PMC

Mell LK, Kochanski JD, Roeske JC, Haslam JJ, Mehta N, Yamada SD, et al. . Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys. (2006) 66:1356–65. 10.1016/j.ijrobp.2006.03.018 PubMed DOI

Torres MA, Jhingran A, Thames HD, Jr, Levenback CF, Bodurka DC, Ramondetta LM, et al. Comparison of treatment tolerance and outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy in a prospective randomized trial or with standard treatment. Int J Radiat Oncol Biol Phys. (2008) 70:118–25. 10.1016/j.ijrobp.2007.05.028 PubMed DOI

Parker K, Gallop-Evans E, Hanna L, Adams M. Five years' experience treating locally advanced cervical cancer with concurrent chemoradiotherapy and high-dose-rate brachytherapy: results from a single institution. Int J Radiat Oncol Biol Phys. (2009) 74:140–6. 10.1016/j.ijrobp.2008.06.1920 PubMed DOI

Peters WA, Liu PY, Barrett RJ, Stock RJ, Monk BJ, Berek JS, et al. . Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. (2000) 18:1606–13. 10.1200/JCO.2000.18.8.1606 PubMed DOI

Rubin P, Landman S, Mayer E, Keller B, Ciccio S. Bone marrow regeneration and extension after extended field irradiation in Hodgkin's disease. Cancer. (1973) 32:699–711. 10.1002/1097-0142(197309)32:3<699::AID-CNCR2820320324>3.0.CO;2-V PubMed DOI

Sacks EL, Goris ML, Glatstein E, Gilbert E, Kaplan HS. Bone marrow regeneration following large field radiation. Influence of volume, age, dose, and time. Cancer. (1978) 42:1057–65. 10.1002/1097-0142(197809)42:3<1057::AID-CNCR2820420304>3.0.CO;2-P PubMed DOI

Yang FE, Vaida F, Ignacio L, Houghton A, Nauityal J, Halpern H, et al. . Analysis of weekly complete blood counts in patients receiving standard fractionated partial body radiation therapy. Int J Radiat Oncol Biol Phys. (1995) 33:607–17. 10.1016/0360-3016(95)00255-W PubMed DOI

Rose BS, Aydogan B, Liang Y, Yeginer M, Hasselle MD, Dandekar V, et al. . Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. (2011) 79:800–7. 10.1016/j.ijrobp.2009.11.010 PubMed DOI PMC

Carmona R, Pritz J, Bydder M, Gulaya S, Zhu H, Williamson CW, et al. . Fat composition changes in bone marrow during chemotherapy and radiation therapy. Int J Radiat Oncol Biol Phys. (2014) 90:155–63. 10.1016/j.ijrobp.2014.05.041 PubMed DOI PMC

Liang Y, Messer K, Rose BS, Lewis JH, Jiang SB, Yashar CM, et al. . Impact of bone marrow radiation dose on acute hematologic toxicity in cervical cancer: principal component analysis on high dimensional data. Int J Radiat Oncol. (2010) 78:912–9. 10.1016/j.ijrobp.2009.11.062 PubMed DOI PMC

Hui B, Zhang Y, Shi F, Wang J, Wang T, Wang J, et al. . Association between bone marrow dosimetric parameters and acute hematologic toxicity in cervical cancer patients undergoing concurrent chemoradiotherapy: comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy. Int J Gynecol Cancer. (2014) 24:1648–52. 10.1097/IGC.0000000000000292 PubMed DOI PMC

Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC, Aydogan B. Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer. Int J Radiat Oncol Biol Phys. (2008) 71:1504–10. 10.1016/j.ijrobp.2008.04.046 PubMed DOI

Li N, Carmona R, Sirak I, Kasaova L, Followill D, Michalski J, et al. . Highly efficient training, refinement, and validation of a knowledge-based planning quality-control system for radiation therapy clinical trials. Int J Radiat Oncol Biol Phys. (2017) 97:164–72. 10.1016/j.ijrobp.2016.10.005 PubMed DOI PMC

Li N, Noticewala SS, Williamson CW, Shen H, Sirak I, Tarnawski R, et al. . Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer. Radiother Oncol. (2017) 123:325–30. 10.1016/j.radonc.2017.02.017 PubMed DOI

Croizat H, Frindel E, Tubiana M. The effect of partial body irradiation on haemopoietic stem cell migration. Cell Prolif. (1980) 13:319–25. 10.1111/j.1365-2184.1980.tb00470.x PubMed DOI

Croizat H, Frindel E, Tubiana M. Proliferative activity of the stem cells in the bone-marrow of mice after single and multiple irradiations (total-or partial-body exposure). Int J Radiat Biol. (1970) 18:347–58. 10.1080/09553007014551191 PubMed DOI

Scarantino CW, Rubin P, Constine LS. The paradoxes in patterns and mechanism of bone marrow regeneration after irradiation. 1. Different volumes and doses. Radiother Oncol. (1984) 2:215–25. 10.1016/S0167-8140(84)80062-6 PubMed DOI

Elicin O, Callaway S, Prior JO, Bourhis J, Ozsahin M, Herrera FG. [18F]FDG-PET standard uptake value as a metabolic predictor of bone marrow response to radiation: impact on acute and late hematological toxicity in cervical cancer patients treated with chemoradiation therapy. Int J Radiat Oncol Biol Phys. (2014) 90:1099–107. 10.1016/j.ijrobp.2014.08.017 PubMed DOI

Fiz F, Marini C, Campi C, Massone AM, Podestà M, Bottoni G, et al. . Allogeneic cell transplant expands bone marrow distribution by colonizing previously abandoned areas: an FDG PET/CT analysis. Blood. (2015) 125:4095–102. 10.1182/blood-2015-01-618215 PubMed DOI

Wyss JC, Carmona R, Karunamuni RA, Pritz J, Hoh CK, Mell LK. [18F]Fluoro-2-deoxy-2-d-glucose versus 3′-deoxy-3′-[18F]fluorothymidine for defining hematopoietically active pelvic bone marrow in gynecologic patients. Radiother Oncol. (2016) 118:72–8. 10.1016/j.radonc.2015.11.018 PubMed DOI PMC

Liang Y, Bydder M, Yashar CM, Rose BS, Cornell M, Hoh CK, et al. . Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies. Int J Radiat Oncol Biol Phys. (2013) 85:406–14. 10.1016/j.ijrobp.2012.04.044 PubMed DOI

Wang Y, Deng W, Li N, Neri S, Sharma A, Jiang W, et al. . Combining immunotherapy and radiotherapy for cancer treatment: Current challenges and future directions. Front Pharmacol. (2018) 9:185. 10.3389/fphar.2018.00185 PubMed DOI PMC

Brixey CJ, Roeske JC, Lujan AE, Yamada SD, Rotmensch J, Mundt AJ. Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys. (2002) 54:1388–96. 10.1016/S0360-3016(02)03801-4 PubMed DOI

Frank L, Basch E, Selby JV. The PCORI perspective on patient-centered outcomes research. JAMA. (2014) 312:1513–4. 10.1001/jama.2014.11100 PubMed DOI